Identification of human-specific amino acid residues governing atenolol transport via organic cation transporter 2.

Organic cation transporter 2 (OCT2/SLC22A2) is predominantly localized on the basolateral membranes of renal tubular epithelial cells and plays a crucial role in the renal secretion of various cationic drugs. Although variations in substrate selectivity among renal organic cation transport systems across species have been reported, the characteristics of OCT2 remain unclear. In this study, we demonstrated that atenolol, a ß1-selective adrenergic antagonist, is transported almost exclusively by human OCT2, contrasting with OCT2s from other selected species. Using chimeric constructs between human OCT2 (hOCT2) and the highly homologous monkey OCT2 (monOCT2), along with site-directed mutagenesis, we identified non-conserved amino acids Val8, Ala31, Ala34, Tyr222, Tyr245, Ala270, Ile394, and Leu503 as pivotal for hOCT2-mediated atenolol transport. Kinetic analysis revealed that atenolol was transported by hOCT2 with a 12-fold lower affinity than MPP+, a typical OCT2 substrate. The inhibitory effect of atenolol on MPP+ transport was 6200-fold lower than that observed for MPP+ on atenolol transport. Additionally, we observed weaker inhibitory effects on MPP+ transport compared to atenolol transport with ten different OCT2 substrates. Altogether, this study suggests that eight hOCT2-specific amino acids constitute the low-affinity recognition site for atenolol transport, indicating differences in OCT2-mediated drug elimination between humans and highly homologous monkeys. Our findings underscore the importance of understanding species-specific differences in drug transport mechanisms, shedding light on potential variations in drug disposition and aiding in drug development.

Which diagnostic test to use for Testing and Treatment strategies in Plasmodium vivax low-transmission settings: a secondary analysis of a longitudinal interventional study.

Background: The lack of sensitive field tests to diagnose blood stages and hypnozoite carriers prevents Testing and Treatment (TAT) strategies to achieve Plasmodium vivax elimination in low-transmission settings, but recent advances in Polymerase Chain Reaction (PCR) and serology position them as promising tools. This study describes a PCR-based TAT strategy (PCRTAT) implemented in Saint Georges (SGO), French Guiana, and explores alternative strategies (seroTAT and seroPCRTAT) to diagnose and treat P. vivax carriers. Methods: The PALUSTOP cohort study implemented in SGO (September 2017 to December 2018) screened participants for P. vivax using PCR tests and treated positive cases. Serology was also performed. Passive detection of P. vivax infection occurred during follow-up. Participants were categorised into overlapping treatment groups based on 2017 PCR and serological results. Strategies were described in terms of participants targeted or missed, primaquine contraindications (pregnancy, G6PD severe or intermediate deficiency), and sociodemographic characteristics. Findings: In 2017, 1567 inhabitants were included, aged 0-92 years. A total of 90 (6%) were P. vivax carriers and 390 seropositive (25%). PCRTAT missed 282 seropositive individuals while seroTAT would have missed 21 PCR-positive cases. Primaquine contraindications ranged from 12% to 17% across strategies. Interpretation: Serology and PCR are promising tools for targeted treatment strategies in P. vivax low-transmission settings, when field compatible sensitive tests will be available. Both seem necessary to capture blood stages and potential hypnozoite carriers, while avoiding mass treatment. However, high primaquine contraindications rates need consideration for successful elimination. Funding: Supported by European Funds for Regional Development, French Guiana Regional Health Agency, Pan American Health Organization, WHO, French Ministry for Research.

Community engagement in mobile and hard-to-reach populations: a community-based intervention for malaria elimination in a tri-national region of the Guiana Shield.

Several countries of the Guiana Shield are aiming at the control and elimination of malaria in areas where Artisanal and Small-scale Gold Mining (ASGM) activities predominate, raising questions about how to strengthen community engagement to improve the effectiveness of health programs. The Curema project focuses its intervention on the mobile and hard-to-reach ASGM population, complementing the efforts of national programs in the Guiana Shield. The Curema intervention combines targeted drug administration for suspected Plasmodium vivax asymptomatic carriers, the Malakit distribution, and health education activities. The primary goals of this manuscript are to outline a pathway to foster community participation in the Curema project aimed at eliminating malaria. Thus, it presents a vision of the challenges that the AGSM community poses in terms of community participation for an asymptomatic problem; and highlights the community-based model and the Information, Education and Communication (IEC) components as foundations for participation. In addition, it also presents culturally sensitive IEC strategies designed through iterative and collaborative consultative processes and other bottom-up outreach activities. The community engagement approach facilitates adaptability and responsiveness in a complex, evolving context increasing the effectiveness of interventions.

Economic Analysis of National Program for Hepatitis C Elimination, Israel, 20231.

In 2021, the Israel Ministry of Health began a national hepatitis C elimination program. Implementing a World Health Organization goal, Israel's program involved targeted screening, barrier minimization, workup simplification, awareness campaigns, and a patient registry. We evaluated program costs for testing and treatment. By May 15, 2023, the program had identified 865,382 at-risk persons, of whom 555,083 (64.3%) were serologically screened for hepatitis C virus (HCV), which was detected in 24,361 (4.4%). Among 20,928 serologically positive patients, viremia was detected in 13,379 (63.9%), of whom 10,711 (80%) were treated, and 4,618 (96.5%) of 4,786 persons receiving posttreatment HCV RNA testing had sustained virologic response. We estimated costs of ₪14,426 (new Israel shekel; ≈$3,606 USD) per person whose HCV infection was diagnosed and successfully treated. The program yielded screening and treatment in almost two thirds of the identified at-risk population. Although not eliminated, HCV prevalence will likely decrease substantially by the 2030 target.

Genome report: Genome sequence of tuliptree scale, Toumeyella liriodendri (Gmelin), an ornamental pest insect.

Scale insects are of interest both to basic researchers for their unique reproductive biology and to applied researchers for their pest status. In spite of this interest, there remain few genomic resources for this group of insects. To begin addressing this lack of data, we present the genome sequence of tuliptree scale, Toumeyella liriodendri (Gmelin) (Hemiptera: Coccomorpha: Coccidae). The genome assembly spans 536Mb, with over 96% of sequence assembled into one of 17 chromosomal scaffolds. We characterize roughly 66% of this sequence as repetitive and annotate 16,508 protein coding genes. Then we use the reference genome to explore the phylogeny of soft scales (Coccidae) and evolution of karyotype within the family. We find that T. liriodendri is an early-diverging soft scale, less closely related to most sequenced soft scales than a species of the family Aclerdidae is. This molecular result corroborates a previous, morphology-based phylogenetic placement of Aclerdidae within Coccidae. In terms of genome structure, T. liriodendri has nearly twice as many chromosomes as the only other soft scale assembled to the chromosome level, Ericerus pela (Chavannes). In comparing the two, we find that chromosome number evolution can largely be explained by simple fissions rather than more complex rearrangements. These genomic natural history observations lay a foundation for further exploration of this unique group of insects.

Hepato-splanchnic fluxes during exercise in patients with cirrhosis-a pilot study.

In cirrhotic patients, compromised hepatocyte function combined with disturbed hepatic blood flow could affect hepato-splanchnic substrate and metabolite fluxes and exacerbate fatigue during exercise. Eight cirrhotic patients performed incremental cycling trials (3 × 10 min; at light (28 [19-37] W; median with range), moderate (55 [41-69] W), and vigorous (76 [50-102] W) intensity). Heart rate increased from 68 (62-74) at rest to 95 (90-100), 114 (108-120), and 140 (134-146) beats/min (P < 0.05), respectively. The hepatic blood flow, as determined by constant infusion of indocyanine green with arterial and hepatic venous sampling, declined from 1.01 (0.75-1.27) to 0.69 (0.47-0.91) L/min (P < 0.05). Hepatic glucose output increased from 0.6 (0.5-0.7) to 1.5 (1.3-1.7) mmol/min, while arterial lactate increased from 0.8 (0.7-0.9) to 9.0 (8.1-9.9) mmol/L (P < 0.05) despite a rise in hepatic lactate uptake. Arterial ammonia increased in parallel to lactate from 47.3 (40.1-54.5) to 144.4 (120.5-168.3) µmol/L (P < 0.05), although hepatic ammonia uptake increased from 19.5 (12.4-26.6) to 69.5 (46.5-92.5) µmol/min (P < 0.05). Among the 14 amino acids measured, glutamate was released in the liver, while the uptake of free fatty acids decreased. During exercise at relatively low workloads, arterial lactate and ammonia levels were comparable to those seen in healthy subjects at higher workloads, while euglycemia was maintained due to sufficient hepatic glucose production. The accumulation of lactate and ammonia may contribute to exercise intolerance in patients with cirrhosis.

Glycosylation of 6-gingerol and unusual spontaneous deglucosylation of two novel intermediates to form 6-shogaol-4'-O-ß-glucoside by bacterial glycosyltransferase.

6-Gingerol is a major phenolic compound within ginger (Zingiber officinale), often used in healthcare; however, its lower bioavailability is partly due to its poor solubility. Four bacterial glycosyltransferases (GTs) were tested to glycosylate 6-gingerol into soluble gingerol glucosides. BsUGT489 was a suitable GT to biotransform 6-gingerol into five significant products, which could be identified via nucleic magnetic resonance and mass spectrometry as 6-gingerol-4',5-O-ß-diglucoside (1), 6-gingerol-4'-O-ß-glucoside (2), 6-gingerol-5-O-ß-glucoside (3), 6-shogaol-4'-O-ß-glucoside (4), and 6-shogaol (5). The enzyme kinetics of BsUGT489 showed substrate inhibition toward 6-gingerol for producing two glucosides. The kinetic parameters were determined as KM (110 µM), kcat (862 min-1), and KI (571 µM) for the production of 6-gingerol-4'-O-ß-glucoside (2) and KM (104 µM), kcat (889 min-1), and KI (545 µM) for the production of 6-gingerol-5-O-ß-glucoside (3). The aqueous solubility of the three 6-gingerol glucosides, compound (1) to (3), was greatly improved. However, 6-shogaol-4'-O-ß-glucoside (4) was found to be a product biotransformed from 6-shogaol (5). This study first confirmed that the glucose moiety at the C-5 position of both 6-gingerol-4',5-O-ß-diglucoside (1) and 6-gingerol-5-O-ß-glucoside (3) caused spontaneous deglucosylation through ß-elimination to form 6-shogaol-4'-O-ß-glucoside (4) and 6-shogaol (5), respectively. Moreover, the GTs could glycosylate 6-shogaol to form 6-shogaol-4'-O-ß-glucoside (4). The assays showed 6-shogaol-4'-O-ß-glucoside (4) had higher anti-inflammatory activity (IC50 value of 10.3 ± 0.2 µM) than 6-gingerol. The 6-gingerol-5-O-ß-glucoside (3) possessed 346-fold higher solubility than 6-shogaol, in which the highly soluble glucoside is a potential prodrug of 6-shogaol via spontaneous deglucosylation. This unusual deglucosylation plays a vital role in influencing the anti-inflammatory activity. IMPORTANCE: Both 6-gingerols and 6-shogaol possess multiple bioactivities. However, their poor solubility limits their application. The present study used bacterial GTs to catalyze the glycosylation of 6-gingerol, and the resulting gingerol glycosides were found to be new compounds with improved solubility and anti-inflammatory activity. In addition, two of the 6-gingerol glucosides were found to undergo spontaneous deglucosylation to form 6-shogaol or 6-shogaol glucosides. The unique spontaneous deglucosylation property of the new 6-gingerol glucosides makes them a good candidate for the prodrug of 6-shogaol.

Comparing efficiencies of population control methods for responding to introductions of transboundary animal diseases in wild pigs.

Introductions of transboundary animal diseases (TADs) into free-ranging wildlife can be difficult to control and devastating for domestic livestock trade. Combating a new TAD introduction in wildlife with an emergency response requires quickly limiting spread of the disease by intensely removing wild animals within a contiguous area. In the case of African swine fever virus (ASFv) in wild pigs (Sus scrofa), which has been spreading in many regions of the world, there is little information on the time- and cost-efficiency of methods for intensively and consistently culling wild pigs and recovering carcasses in an emergency response scenario. We compared the efficiencies of aerial operations, trapping, experimental toxic baiting, and ground shooting in northcentral Texas, USA during two months in 2023. Culling and recovering carcasses of wild pigs averaged a rate of 0.15 wild pigs/person hour and cost an average of $233.04/wild pig ($USD 2023) across all four methods. Aerial operations required the greatest initial investment but subsequently was the most time- and cost-efficient, costing an average of $7266 to reduce the population by a standard measure of 10 %, including recovering carcasses. Aerial operations required a ground crew of ∼7 people/helicopter to recover carcasses. Costs for reducing the population of wild pigs using trapping were similar, although took 13.5 times longer to accomplish. In cases where carcass recovery and disposal are needed (e.g., response to ASFv), a benefit of trapping was immediate carcass recovery. Toxic baiting was less efficient because both culling and carcass recovery required substantial time. We culled very few wild pigs with ground shooting in this landscape. Our results provide insight on the efficiencies of each removal method. Strategically combining removal methods may increase overall efficiency. Overall, our findings inform the preparation of resources, personnel needs, and deployment readiness for TAD responses involving wild pigs.

[Progress of interruption of schistosomiasis transmission and prospects in Yunnan Province].

Schistosomiasis was once hyper-endemic in Yunnan Province. Following concerted efforts for over 70 years, remarkable achievements have been made for schistosomiasis control in the province. In 2004, the Mid- and Long-term Plan for Schistosomiasis Prevention and Control in Yunnan Province was initiated in Yunnan Province, and the target for transmission control of schistosomiasis was achieved in the province in 2009. Following the subsequent implementation of the Outline for Key Projects in Integrated Schistosomiasis Control Program (2009-2015) and the 13th Five - year Plan for Schistosomiasis Control in Yunnan Province, no acute schistosomiasis had been identified in Yunnan Province for successive 12 years, and no local Schistosoma japonicum infections had been detected in humans, animals or Oncomelania hupensis snails for successive 6 years in the province by the end of 2020. The transmission of schistosomiasis was interrupted in Yunnan Province in 2020. This review summarizes the history of schistosomiasis, changes in schistosomiasis prevalence and progress of schistosomiasis control in Yunnan Province, and proposes the future priorities for schistosomiasis control in the province.

CUREMA project: a further step towards malaria elimination among hard-to-reach and mobile populations.

BACKGROUND: In most countries engaged on the last mile towards malaria elimination, residual transmission mainly persists among vulnerable populations represented by isolated and mobile (often cross-border) communities. These populations are sometimes involved in informal or even illegal activities. In regions with Plasmodium vivax transmission, the specific biology of this parasite poses additional difficulties related to the need for a radical treatment against hypnozoites to prevent relapses. Among hard-to-reach communities, case management, a pillar of elimination strategy, is deficient: acute malaria attacks often occur in remote areas, where there is limited access to care, and drugs acquired outside formal healthcare are often inadequately used for treatment, which typically does not include radical treatment against P. vivax. For these reasons, P. vivax circulation among these communities represents one of the main challenges for malaria elimination in many non-African countries. The objective of this article is to describe the protocol of the CUREMA study, which aims to meet the challenge of targeting malaria in hard-to-reach populations with a focus on P. vivax. RESULTS: CUREMA is a multi-centre, international public health intervention research project. The study population is represented by persons involved in artisanal and small-scale gold mining who are active and mobile in the Guiana Shield, deep inside the Amazon Forest. The CUREMA project includes a complex intervention composed of a package of actions: (1) health education activities; (2) targeted administration of treatment against P. vivax after screening against G6PD deficiency to asymptomatic persons considered at risk of silently carrying the parasite; (3) distribution of a self-testing and self-treatment kit (malakit) associated with user training for self-management of malaria symptoms occurring while in extreme isolation. These actions are offered by community health workers at settlements and neighbourhoods (often cross-border) that represent transit and logistic bases of gold miners. The study relies on hybrid design, aiming to evaluate both the effectiveness of the intervention on malaria transmission with a pre/post quasi-experimental design, and its implementation with a mixed methods approach. CONCLUSIONS: The purpose of this study is to experiment an intervention that addresses both Plasmodium falciparum and P. vivax malaria elimination in a mobile and isolated population and to produce results that can be transferred to many contexts facing the same challenges around the world.

Understanding Cytochrome P450 Enzyme Substrate Inhibition and Prospects for Elimination Strategies.

Cytochrome P450 (CYP450) enzymes, which are widely distributed and pivotal in various biochemical reactions, catalyze diverse processes such as hydroxylation, epoxidation, dehydrogenation, dealkylation, nitrification, and bond formation. These enzymes have been applied in drug metabolism, antibiotic production, bioremediation, and fine chemical synthesis. Recent research revealed that CYP450 catalytic kinetics deviated from the classic Michaelis-Menten model. A notable substrate inhibition phenomenon that affects the catalytic efficiency of CYP450 at high substrate concentrations was identified. However, the substrate inhibition of various reactions catalyzed by CYP450 enzymes have not been comprehensively reviewed. This review describes CYP450 substrate inhibition examples and atypical Michaelis-Menten kinetic models, and provides insight into mechanisms of these enzymes. We also reviewed 3D structure and dynamics of CYP450 with substrate binding. Outline methods for alleviating substrate inhibition in CYP450 and other enzymes, including traditional fermentation approaches and protein engineering modifications. The comprehensive analysis presented in this study lays the foundation for enhancing the catalytic efficiency of CYP450 by deregulating substrate inhibition.

Rapid elimination of scattering in three-dimensional fluorescence spectra via deep learning.

Three-dimensional fluorescence spectra are often affected by scattering effects, traditional scattering elimination methods rely excessively on parameter settings and cannot automatically eliminate scattering in batches, thereby limiting the application of fluorescence spectroscopy technology in rapid online monitoring and analysis of samples. In this study, we have developed a model based on a deep learning CycleGAN to rapidly eliminate scattering from three-dimensional fluorescence spectra. The proposed model efficiently eliminates scattering by simply inputting single or batches of contaminated fluorescent spectra. By training the CycleGAN using a large dataset of simulated three-dimensional fluorescence spectra and employing data augmentation, to the model can transform fluorescence spectra with scattering into ones without scattering. To validate the effectiveness of the proposed methed, we confirmed its generalization and reliability by eliminating scattering from two sets of previously unseen real experimental three-dimensional fluorescence spectra. We evaluated the effectiveness of scattering elimination across various noise levels and scattering widths, using metrics such as the mean absolute error, peak signal-to-noise ratio, structural similarity and cosine similarity. Furthermore, we conducted a component analysis using PARAFAC on the spectra post-scattering elimination, yielding correlation coefficients of >0.97 when compared to that in case of actual components. Finally, we compared the proposed model with traditional mathematical methods, such as blank subtraction and Delaunay triangulation. Results showed that the proposed model can automatically and efficiently eliminate scattering from fluorescence spectra in batches, substantially improving the efficiency of scattering elimination.

One-food versus 4-food elimination diet for pediatric eosinophilic esophagitis: A multisite randomized trial.

BACKGROUND: A 6-food elimination diet in pediatric eosinophilic esophagitis (EoE) is difficult to implement and may negatively affect quality of life (QoL). Less restrictive elimination diets may balance QoL and efficacy. OBJECTIVE: We performed a multisite, randomized comparative efficacy trial of a 1-food (milk) elimination diet (1FED) versus 4-food (milk, egg, wheat, soy) elimination diet (4FED) in pediatric EoE. METHODS: Patients aged 6 to 17 years with histologically active and symptomatic EoE were randomized 1:1 to 1FED or 4FED for 12 weeks. Primary end point was symptom improvement by Pediatric Eosinophilic Esophagitis Symptom Score (PEESS). Secondary end points were proportion experiencing histologic remission (<15 eosinophils per high-power field); change in histologic features (histology scoring system), endoscopic severity (endoscopic reference score), transcriptome (EoE diagnostic panel), and QoL scores; and predictors of remission. RESULTS: Sixty-three patients were randomly assigned to 1FED (n = 38) and 4FED (n = 25). In 4FED versus 1FED, mean PEESS improved -25.0 versus -14.5 (P = .04), but remission rates (41% vs 44%; P = 1.00), histology scoring system (-0.25 vs -0.29; P = .77), endoscopic reference score (-1.10 vs -0.58; P = .47), and QoL scores were similar between groups. The EoE transcriptome normalized in those with histologic response to both diets. Baseline peak eosinophil count predicted remission (odds ratio, 0.975 [95% confidence interval, 0.953-0.999], P = .04; cutoff ≤42 eosinophils per high-power field). The 4FED withdrawal rate (32%) exceeded that of 1FED (11%) (P = .0496). CONCLUSIONS: Although 4FED moderately improved symptoms compared with 1FED, the histologic, endoscopic, QoL, and transcriptomic outcomes were similar in both groups. 1FED is a reasonable first-choice therapy for pediatric EoE, given its effects, tolerability, and relative simplicity.

Community-Wide Active Case Finding for Tuberculosis: Time to Use the Evidence We Have.

Tuberculosis, caused by the Mycobacterium tuberculosis (Mtb) bacteria, is one of the world's deadliest infectious diseases. Despite being the world's oldest pandemic, tuberculosis is very much a challenge of the modern era. In high-incidence settings, all people are at risk, irrespective of whether they have common vulnerabilities to the disease warranting the current WHO recommendations for community-wide tuberculosis active case finding in these settings. Despite good evidence of effectiveness in reducing tuberculosis transmission, uptake of this strategy has been lacking in the communities that would derive greatest benefit. We consider the various complexities in eliminating tuberculosis from the first principles of the disease, including diagnostic and other challenges that must be navigated under an elimination agenda. We make the case that community-wide tuberculosis active case finding is the best strategy currently available to drive elimination forward in high-incidence settings and that no time should be lost in its implementation. Recognizing that high-incidence communities vary in their epidemiology and spatiosocial characteristics, tuberculosis research and funding must now shift towards radically supporting local implementation and operational research in communities. This "preparing of the ground" for scaling up to community-wide intervention centers the local knowledge and local experience of community epidemiology to optimize implementation practices and accelerate reductions in community-level tuberculosis transmission.

Implementing a new HCV model of care for people who use drugs.

Background & Aims: An estimated 50 million individuals have chronic hepatitis C virus (HCV) infection worldwide and people who use drugs (PWUD) are disproportionately affected. Persistent stigma and discrimination make it challenging for PWUD to access healthcare, potentially hindering HCV elimination progress in this population. To mitigate healthcare access barriers in PWUD, an HCV care model that simplified screening and linkage to care pathways was developed and rolled out in the Balearic Islands, Spain. Methods: The prospective multicentre community model of care was implemented in 21 centres serving PWUD. This model involved: (1) participant recruitment and HCV antibody screening onsite via a point-of-care anti-HCV test, phlebotomy, or laboratory records; (2) HCV RNA, HBsAg and anti-HIV testing via a dried blood spot or phlebotomy; (3) linkage to specialist care and treatment prescription via telemedicine, when required; and (4) onsite monitoring of: (a) sustained virologic response (SVR) 4 and ≥12 weeks after treatment completion and; (b) potential new HCV infection or reinfection ∼1 year after phase 1 or SVR ≥12 monitoring. Care model acceptability was assessed. Results: Between April 2021 and April 2023, 1,423 participants were recruited, of whom 464 (33%) were anti-HCV+ and 170 (12%) had detectable HCV RNA. Of the latter, 147 (86%) initiated therapy, of whom 124 (84%) completed it. SVR ≥12 monitoring was performed in 95 (77%) of these, of whom 88 (93%) had undetectable HCV RNA. Upon re-screening, four HCV reinfections were detected. Over 90% accepted study participation and screening and treatment decentralisation. Conclusions: This adapted care model, which decentralised screening, diagnosis, and treatment, effectively increased healthcare access among PWUD, improving progress towards HCV elimination in this population in Spain. Impact and implications: People who use drugs (PWUD) are among the most affected by chronic hepatitis C virus (HCV) infection globally. A simplified model of care was implemented in 21 centres serving this population across the Balearic Islands, Spain, to offer HCV care to 1,423 PWUD in 2021-2023. This decentralised screening, diagnosis, and treatment model resulted in an HCV cure rate of 93% of those who both completed therapy and were monitored post treatment completion. The Hepatitis C Free Balears model can guide the HCV elimination efforts of regional health authorities and other stakeholders in the rest of Spain and other parts of the world.

Effectiveness and implementation of decentralized, community- and primary care-based strategies in promoting hepatitis B testing uptake: a systematic review and meta-analysis.

Background: Expanding chronic hepatitis B (CHB) testing through effective implementation strategies in primary- and community-care setting is crucial for elimination. Our study aimed to determine the effectiveness of all available strategies in the literature and evaluate their specifications and implementation outcomes, thereby informing future programming and policymaking. Methods: We conducted a systematic review and meta-analysis (PROSPERO CRD42023455781), searching Scopus, Embase, PubMed, and CINAHL databases up to June 05, 2024, for randomized controlled trials investigating primary- and community-care-based implementation strategies to promote CHB testing. Studies were screened against a priori eligibility criteria, and their data were extracted using a standardized protocol if included. ROB-2 was used to assess the risk of bias. Implementation strategies' components were characterized using the Behavior Change Wheel (BCW) framework. Random-effect models were applied to pool the effectiveness estimate by strategy. Mixed-effect meta-regression was employed to investigate if effectiveness varied by the number of strategy's BCW components. Findings: 7146 unique records were identified. 25 studies were eligible for the review, contributing 130,598 participants. 19 studies were included in the meta-analysis. No studies were conducted in low-and-middle-income countries. Implementation outcomes were reported in only ten studies (40%). Community-based strategies included lay health workers-led education (Pooled Risk Difference = 27.9% [95% Confidence Interval = 3.4-52.4], I2 = 99.3%) or crowdsourced education on social media (3.1% [-2.2 to 8.4], 0.0%). Primary care-based strategies consisted of electronic alert system (8.4% [3.7-13.1], 95.0%) and healthcare providers-led education (HCPs, 62.5% [53.1-71.9], 27.5%). The number of BCW-framework-driven strategy components showed a significant dose-response relationship with effectiveness. Interpretation: HCPs-led education stands out, and more enriched multicomponent strategies had better effectiveness. Future implementation strategies should consider critical contextual factors and policies to achieve a sustainable impact towards hepatitis B elimination targets. Funding: Tran Dolch Post-Doctoral Fellowship in Hepatology, Johns Hopkins University School of Medicine, Baltimore MD, USA.

Detection of Schizophrenia from EEG Signals using Selected Statistical Moments of MFC Coefficients and Ensemble Learning.

Schizophrenia is a mental disorder characterized by neurophysiological dysfunctions that result in disturbances in thinking, perception, and behavior. Early identification of schizophrenia can help prevent potential complications and facilitate effective treatment and management of the condition. This paper proposes a computer aided diagnosis system for the early detection of schizophrenia using 19-channel Electroencephalography (EEG) signals from 28 subjects, leveraging statistical moments of Mel-frequency Cepstral Coefficients (MFCC) and ensemble learning. Initially, the EEG signals are passed through a high-pass filter to mitigate noise and remove extraneous data. The feature extraction technique is then employed to extract MFC coefficients from the filtered EEG signals. The dimensionality of these coefficients is reduced by computing their statistical moments, which include the mean, standard deviation, skewness, kurtosis, and energy. Subsequently, the Support Vector Machine based Recursive Feature Elimination (SVM-RFE) is applied to identify pertinent features from the statistical moments of the MFC coefficients. These SVM-RFE-based selected features serve as input for three base classifiers: Support Vector Machine, k-Nearest Neighbors, and Logistic Regression. Additionally, an ensemble learning approach, which combines the predictions of the three classifiers through majority voting, is introduced to enhance schizophrenia detection performance and generalize the results of the proposed approach. The study's findings demonstrate that the ensemble model, combined with SVM-RFE-based selected statistical moments of MFCC, achieves encouraging detection performance, highlighting the potential of machine learning techniques in advancing the diagnostic process of schizophrenia.

Exploration of uricase-like activity in Pd@Ir nanosheets and their application in relieving acute gout using self-cascade reaction.

Gout, marked by the deposition of sodium urate crystals in joints and peripheral tissues, presents a considerable health challenge. Recent research has shown a growing interest in nanozyme-based treatments for gout. However, literature on nanozymes that combine uricase-like (UOX) activity for uric acid (UA) degradation with catalase (CAT)-like activity for H2O2 elimination through a self-cascade reaction is limited. Herein, we discovered that two-dimensional Pd@Ir nanosheets (NSs) exhibit UOX and CAT activities effectively. Notably, we observed a size-dependent effect of Pd@Ir on activation energy during UA degradation, with the larger Pd@Ir NSs demonstrating a lower energy barrier. The 46-nm Pd@Ir had activation energy as low as 35.9 kJ/mol, surpassing the efficiency of natural bacterial uricase and most reported nanozymes. Through a tandem self-cascade reaction of Pd@Ir, UA was effectively degraded via UOX activity, while the byproduct H2O2 was simultaneously eliminated by CAT-like activity. Cell experiments revealed that Pd@Ir protect normal cells from oxidative stress and promote cell proliferation, demonstrating an excellent self-cascade effect. Additionally, Pd@Ir substantially alleviated gout symptoms in monosodium urate-induced acute gout mice without causing toxic effects on biological organs and tissues. This study opens new avenues for using nanozyme-based cascade reaction systems in the treatment of metabolic diseases.

Early therapeutic drug monitoring of methotrexate and its association with acute kidney injury: A retrospective cohort study.

INTRODUCTION: High-dose methotrexate (HDMTX) use can be limited by the development of acute kidney injury (AKI). Early AKI detection is paramount to prevent further renal injury and irreversible toxicities. This study sought to determine whether early elimination patterns of MTX would be useful as a biomarker of AKI in HDMTX treatment. METHODS: This retrospective cohort study included two sites that collected ≥2 MTX levels within 16 h from completion of MTX infusion. Early levels were tagged and MTX elimination half-life (t½) were calculated from combinations of two of three different early time periods. Receiver operating characteristic (ROC) curves were synthesized for each elimination t½ (biomarker) with respect to AKI and delayed methotrexate elimination (DME); the biomarker with the highest area under the ROC curve (AUC) was tested in a multiple variable logistic regression model. RESULTS: Data from 169 patients who received a total of 556 courses of HDMTX were analyzed. ROC analysis revealed MTX elimination t½ calculated from the second and third time periods had the highest AUC for AKI at 0.62 (interquartile range [IQR] 0.56-0.69) and DME at 0.86 (IQR 0.73-1.00). After adjusting for age, sex, dose (mg/m2), infusion duration, HDMTX course, and baseline estimated glomerular filtration rate, it remained significant for AKI with an OR of 1.29 and 95% confidence interval of 1.03-1.65. CONCLUSION: Early MTX elimination t½ measured within 16 h of infusion completion was significantly associated with the development of AKI and serves as an early clearance biomarker that may identify patients who benefit from increased hydration, augmented leucovorin rescue, and glucarpidase administration.

Methods for degrading dicloxacillin in water using inorganic peroxides and their combination with UVC- experimental and theoretical aspects.

Antibiotics are currently recognized as environmental pollutants. In this work, the methods involved in the degradation of a ß-lactam antibiotic (i.e., DXC) by treatments based on inorganic peroxides and UVC (e.g., UVC alone, UV-C/H2O2, UVC/peroxymonosulfate, and UVC/peroxydisulfate) are presented. The methodology of computational calculations to obtain frontier orbitals and Fukui indices for DXC, and elucidate the reactive moieties on the target substance is also shown. Finally, the direct oxidation by peroxides and UV-C/H2O2 action to treat DXC in simulated pharmaceutical wastewater are depicted. The chromatographic and theoretical analyses allowed for determining the degrading performance of inorganic peroxides and UVC-based treatments toward the target pollutant in aqueous samples.•Treatments based on inorganic peroxides and UVC as useful methods for degrading the ß-lactam antibiotic dicloxacillin.•Persulfates and UV-C/H2O2 showed high degrading action on the target pharmaceutical.•Methodologies based on theoretical calculations for the identification of reactive moieties on the DXC susceptible to radical attacks are presented.